The invention relates to peptides for the treatment and early diagnosis of Alzheimer's disease and other tauopathies.
Alzheimer's disease (AD) is characterized by the pathological aggregation of two proteins, the Aβ peptide (amyloid beta peptide, Abeta peptide) and the tau protein. Both kinds of protein aggregations are considered neurotoxic, while the respective monomers are not toxic or have important functions in vertebrate cells.
In vertebrate cells, the tau protein binds to supporting cytoskeleton proteins (microtubules) and regulates the assembly of the same. The group of tauopathies covers neurodegenerative diseases involving deposits of the tau protein. The most widely known tauopathy is Alzheimer's disease. However, pathological tau aggregates also occur in 17 other diseases, such as frontotemporal dementia and Parkinson's disease. In some instances, a mutated tau protein is the only main feature in terms of pathology.
Various isoforms of the tau protein can be found in the human central nervous system. Tau proteins can agglomerate and form abnormal “paired helical filaments” (PHF). As a result of these pathological changes, PHF deposits can be observed as neurofibrillary tangles in the brains of Alzheimer patients. Since aggregated tau proteins are no longer functional, the assembly of the microtubules is disrupted.
Small molecules that are intended to prevent tau protein aggregation were already described. However, they are low in numbers compared to molecules that are intended to prevent, or reverse, Aβ aggregation. Of late, since treating Alzheimer's by solely focusing on Aβ aggregates may not be able to produce the desired success, the tau protein and the interaction thereof with the Aβ peptide have been increasingly addressed in the literature. For example, reducing the plaque content through anti-Aβ immunotherapy has not resulted in the expected improvements in the cognitive capabilities of the treated patients. Many scientists meanwhile even ascribe a neuroprotective effect to Aβ.
Tau aggregation inhibitors and modulators can potentially complement existing therapeutic experiments. While the cause of the tau aggregation cascade remains unknown to this day, a close correlation exists between the number of neurofibrillary tangles in the neurons, cellular degeneration, and the symptoms of dementia.
Preliminary data from phase 2 clinical studies demonstrate that the inhibition of tau aggregation is useful for treating AD. Rhodanine-based inhibitors resulted in a clear reduction of tau aggregation-based cytotoxicity in the cytosol of neuronal cell models. In phase IIa clinical studies, AL-108, the intranasal formulation of the NAP peptide consisting of eight amino acids, was found to have a positive influence on the memory capacity of patients with amnestic mild cognitive impairment (aMCI). A direct influence on the hyperphosphorylation of tau was shown for NAP, among other things, initial studies substantiate successes after tau-based immunotherapy of transgenic mouse models. Tau-based therapies will play an ever greater role in the future, since tau aggregates have infectious properties. The pathological tau aggregation can be passed on from one cell to another. In addition, tau-expressing mouse models show a clearer pathology after artificial infection with tau aggregates.
In addition to therapeutic components, there is an urgent need for improved diagnostic methods for AD. So far, a variety of substances that bind to aggregated Aβ peptide exist. Following the incorporation of radionuclides into these substances, imaging methods such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) can be carried on the live patent (“in vivo imaging”). Since the amount of plaque has little correlation with the progression of AD, substances that bind with high specificity to tau aggregates potentially provide a diagnostic alternative, since the occurrence of neurofibrillary tau tangles correlates with the progression of the disease. So far, only few substances have been described which selectively bind in vitro to the aggregated tau protein. Quinoline and benzimidazole derivatives selectively stained neurofibrillary tangles in brain sections of deceased AD patients.
The disadvantage is that, so far, only symptoms of AD can be treated. No approved medications exist which can stop or reverse the disease process. The majority of substances being explored for AD treatment focus on extracellular Aβ, but not on tau pathology or, preferably, on both.